Without limiting the scope of the invention, its background is described in connection with existing siRNA based therapies. SiRNA-based therapies have shown promise in recent clinical trials as anti-cancer agents. See Tabernero, J. et al. “First-in-humans trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement” Cancer Discov. 3, 406-417 (2013). This technology offers tremendous potential in silencing “non-druggable” targets that are not amenable to conventional therapeutics such as small molecules or monoclonal antibodies. However, the lack of stability and low potency at target sites following systemic administration remain the major obstacles to clinical translation of this therapy. See e.g. Pecot, C., et al. “RNA interference in the clinic: challenges and future directions” Nat. Rev. Cancer 11, 59-67 (2011).
To overcome these problems, efforts have been made to chemically modify the 2′-position of the ribose moiety (e.g. 2′-OMe or 2′-F) or phosphate backbone of the siRNA molecule (e.g. phosphoromonothioate (PS) modification) such that enhanced serum stability, bioavailability, and prolonged duration of action could be achieved. See e.g. Behlke, M. A. “Progress towards in vivo use of siRNAs” Mol. Ther. 13, 644-670 (2006). Importantly, combining PS and 2′-modification impart superior stability over single modifications leading to the approval of Kynamro, an antisense therapeutic, by the Food and Drug Administration. See Stein, D., et al. “A specificity comparison of four antisense types: morpholino, 2′-O-methyl RNA, DNA, and phosphorothioate DNA” Antisense Nucleic Acid Drug Dev. 7, 151-157 (1997).
Despite the advance, the combination of PS and 2′-modification shows limited enhancement of siRNA potency. See e.g. Prakash, T. et al. “Positional effect of chemical modifications on short interference RNA activity in mammalian cells” J. Med. Chem. 48, 4247-4253 (2005).
From the foregoing it is apparent the there is a need in the art for improved strategies for the chemical modification of siRNAs such that their therapeutic potential can be realized.